Stromal oncostatin M cytokine promotes breast cancer progression by reprogramming the tumor microenvironment
Angela M. Araujo, … , María M. Caffarel, Charles H. Lawrie
Angela M. Araujo, … , María M. Caffarel, Charles H. Lawrie
Published February 22, 2022
Citation Information: J Clin Invest. 2022;132(7):e148667. https://doi.org/10.1172/JCI148667.
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Research Article Inflammation Oncology

Stromal oncostatin M cytokine promotes breast cancer progression by reprogramming the tumor microenvironment

Abstract

The tumor microenvironment (TME) is reprogrammed by cancer cells and participates in all stages of tumor progression. The contribution of stromal cells to the reprogramming of the TME is not well understood. Here, we provide evidence of the role of the cytokine oncostatin M (OSM) as central node for multicellular interactions between immune and nonimmune stromal cells and the epithelial cancer cell compartment. OSM receptor (OSMR) deletion in a multistage breast cancer model halted tumor progression. We ascribed causality to the stromal function of the OSM axis by demonstrating reduced tumor burden of syngeneic tumors implanted in mice lacking OSMR. Single-cell and bioinformatic analysis of murine and human breast tumors revealed that OSM expression was restricted to myeloid cells, whereas OSMR was detected predominantly in fibroblasts and, to a lower extent, cancer cells. Myeloid-derived OSM reprogrammed fibroblasts to a more contractile and tumorigenic phenotype and elicited the secretion of VEGF and proinflammatory chemokines CXCL1 and CXCL16, leading to increased myeloid cell recruitment. Collectively, our data support the notion that the stromal OSM/OSMR axis reprograms the immune and nonimmune microenvironment and plays a key role in breast cancer progression.

Authors

Angela M. Araujo, Andrea Abaurrea, Peio Azcoaga, Joanna I. López-Velazco, Sara Manzano, Javier Rodriguez, Ricardo Rezola, Leire Egia-Mendikute, Fátima Valdés-Mora, Juana M. Flores, Liam Jenkins, Laura Pulido, Iñaki Osorio-Querejeta, Patricia Fernández-Nogueira, Nicola Ferrari, Cristina Viera, Natalia Martín-Martín, Alexandar Tzankov, Serenella Eppenberger-Castori, Isabel Alvarez-Lopez, Ander Urruticoechea, Paloma Bragado, Nicholas Coleman, Asís Palazón, Arkaitz Carracedo, David Gallego-Ortega, Fernando Calvo, Clare M. Isacke, María M. Caffarel, Charles H. Lawrie

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Figure 5

OSM activates cancer-associated fibroblasts (CAFs) in vitro, promoting their contractility and proliferation.

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OSM activates cancer-associated fibroblasts (CAFs) in vitro, promoting t...
(A and B) Representative pictures of collagen contraction assays (A) and quantification of collagen disk areas (B) of fibroblasts pretreated in monolayer with PBS or OSM. (C and D) Representative pictures (C) and area quantification (D) of 3D sphere proliferation assays of fibroblasts treated with PBS or OSM. Scale bars: 200 μm. In B and D, 2 independent experiments are plotted (experiments 1 and 2) and P values were calculated using the unpaired, 2-tailed Student’s t test. (E) RT-qPCR analysis of mRNA levels of activation markers in normal fibroblasts (RMF-31) and CAFs (CAF-173) cultured in 3D with PBS or OSM. n = 3 independent experiments. P values were determined using paired, 2-tailed Student’s t tests. (F) Gene set enrichment analysis (GSEA) showing enrichment of the indicated signatures in microarray data of CAF-173 treated with OSM. Data for the fibroblast activation signature were derived from Sahai et al. (4). NES, normalized enrichment score. (G) Kaplan-Meier curves showing overall survival (OS) for breast cancer patients according to the high or low expression in tumor samples of top 4 genes induced by OSM in CAF-173. Data were obtained using the Kaplan-Meier Plotter website. P value was calculated using the Mantel-Cox test and high and low expression levels were stratified by median values.